Bush Ashley I
Oxidation Disorders Research Unit, Mental Health Research Institute of Victoria, University of Melbourne, 155 Oak Street, Parkville VIC 3052, Australia.
Neurobiol Aging. 2002 Nov-Dec;23(6):1031-8. doi: 10.1016/s0197-4580(02)00120-3.
Modern research approaches into drug development for Alzheimer's disease (AD) target beta-amyloid (Abeta) accumulation in the brain. The main approaches attempt to prevent Abeta production (secretase inhibitors) or to clear Abeta (vaccine). However, there is now compelling evidence that Abeta does not spontaneously aggregate, but that there is an age-dependent reaction with excess brain metal (copper, iron and zinc), which induces the protein to precipitate into metal-enriched masses (plaques). The abnormal combination of Abeta with Cu or Fe induces the production of hydrogen peroxide, which may mediate the conspicuous oxidative damage to the brain in AD. We have developed metal-binding compounds that inhibit the in vitro generation of hydrogen peroxide by Abeta, as well as reverse the aggregation of the peptide in vitro and from human brain post-mortem specimens. Most recently, one of the compounds, clioquinol (CQ; a USP antibiotic) was given orally for 9 weeks to amyloid-bearing transgenic mice, and succeeded in markedly inhibiting Abeta accumulation. On the basis of these results, CQ is being tested in clinical trials.
针对阿尔茨海默病（AD）的药物研发，现代研究方法聚焦于大脑中β-淀粉样蛋白（Aβ）的积聚。主要方法包括试图阻止Aβ的产生（分泌酶抑制剂）或清除Aβ（疫苗）。然而，现在有确凿证据表明，Aβ不会自发聚集，而是与过量的脑内金属（铜、铁和锌）发生年龄依赖性反应，这种反应会促使该蛋白沉淀形成富含金属的团块（斑块）。Aβ与铜或铁的异常结合会诱导过氧化氢的产生，而过氧化氢可能介导了AD患者大脑中明显的氧化损伤。我们已经研发出金属结合化合物，它们能够抑制Aβ在体外产生过氧化氢，并且能在体外以及从人脑尸检标本中逆转该肽的聚集。最近，其中一种化合物氯碘羟喹（CQ；一种美国药典收录的抗生素）对携带淀粉样蛋白的转基因小鼠进行了为期9周的口服给药，并成功显著抑制了Aβ的积聚。基于这些结果，CQ正在进行临床试验。
